Alveolar type 2 cell LRP1 is needed for surfactant phospholipids and pulmonary function in mice

The low-density lipoprotein receptor related protein 1 (LRP1) performs multiple functions with cell-specific regulation. Genetic variants in LRP1 are associated with chronic obstructive pulmonary disease (COPD), but the underlying mechanisms are unknown. Surfactant lipid metabolism is impacted by COPD. To investigate LRP1 in alveolar type 2 cells (T2C), we stably transfected a cell line of human T2C with LRP1-shRNA (LRP1 knockdown, LRP1 KD), and generated T2C-specific LRP1 knockout mice (SPC-LRP1-/-). LRP1 KD cells showed decreased surfactant phospholipid secretion and increased neutral lipid accumulation, despite lower expression of lipid metabolic genes. T2C and alveolar surfactant isolated from SPC-LRP1-/- mice showed lower concentrations of phosphatidylcholine than those from Lrp1-floxed controls. At baseline, SPC-LRP1-/- decreased lung compliance and forced vital capacity. After smoke exposure, SPC-LRP1-/- showed worse pulmonary function and emphysema than control mice. RNA sequencing revealed that loss of LRP1 in T2C increased gene expression of detoxification and inflammatory pathways associated with COPD. Finally, query of public human data showed that T2C from patients with COPD have lower expression of LRP1 and lipid metabolic genes . This study shows that LRP1 in T2C is needed for surfactant lipid metabolism and pulmonary function, and it suggests that reductions of LRP1 expression promote COPD.